Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Removal of inflammatory cells from an inflamed tissue is a prerequisite for resolution and return to normal structure and function. Removal of neutrophils is hypothesized to involve apoptosis in situ with subsequent recognition and uptake by macrophages in a process that selectively initiates production of anti-inflammatory signals such as TGFbeta and PGE/2 to switch off further generation of pro-inflammatory mediators and hasten the resolution. These hypothesis will be examined during resolution of pulmonary inflammation in the mouse. Two signalling pathways leading to neutrophil apoptosis have been identified, one of which may involve fas and fas ligand (fasL). A preliminary observation of enhanced inflammation in the lungs of fas-deficient mice supports the central hypothesis and the possible involvement of the fast-fasL system. Inflammatory reactions of defined duration will be induced in mice by the chemokine KC, lipopolysaccharide or bleomycin and the role of neutrophil apoptosis in resolution examined. Neutrophils have a short lifespan after release from the bone marrow which implies a tremendous turnover rate and raises the question of normal sites and mechanisms of removal from the circulation as well as from inflammatory reactions. The possible presence of a built-in time clock in neutrophils leading inexorable to apoptosis in either blood or inflammatory reactions will be distinguished from an alternative concept; namely that the cells accumulate in liver and spleen (sites of "physiologic" removal) or inflammation and are there actively induced to undergo apoptosis by local signals such as fasL. Approaches to these questions will involve a combination of biochemical, morphologic, pathological and genetic techniques, both in vitro and during pulmonary inflammation in whole animals. Neutrophils will be labelled and re-infused into the blood or inflammatory reactions to determine apoptosis, distribution and disposition. Blockade of specific reactions (such as fas/fasL) will be achieved by administration of antibodies or use of genetically deficient mice. The role of anti-inflammatory mediators will be explored by identification of their presence, blockade of their effect and assessment of the inflammatory response after their direct administration. Central to these proposed studies is the suggestion that only by understanding the mechanisms for resolution of acute self-limited inflammatory reaction will be able to approach abnormalities of the resolution process that contribute to chronic persistent inflammation underling a majority of human pulmonary diseases.
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